Association between the use of lipid‐lowering drugs and the risk of inflammatory bowel disease

Abstract

BackgroundObservational studies have suggested an association between lipid‐lowering drugs and inflammatory bowel disease (IBD) risk. This study aimed to assess the causal influence of lipid‐lowering agents on IBD risk using Mendelian randomization analysis.MethodIn a population of 173,082 individuals of European ancestry, 55 single‐nucleotide polymorphisms were identified as instrumental variables for 6 lipid‐lowering drug targets (HMGCR, NPC1LC, PCSK9, LDLR, CETP and APOB). Summary statistics for the genome‐wide association study of IBD, ulcerative colitis (UC) and Crohn's disease (CD) were obtained from the FinnGen consortium, Program in Complex Trait Genomics and UK Biobank. Inverse‐variance weighted was employed as the primary MR method, and odds ratios (ORs) with 95% confidence intervals were reported as the results. Sensitivity analyses using conventional MR methods were conducted to assess result robustness.ResultsGene‐proxied inhibition of Niemann‐Pick C1‐like 1 (NPC1L1) was associated with an increased IBD risk (OR [95% CI]: 2.31 [1.38, 3.85]; p = .001), particularly in UC (OR [95% CI]: 2.40 [1.21, 4.74], p = .012), but not in CD. This finding was replicated in the validation cohort. Additionally, gene‐proxied inhibition of low‐density lipoprotein receptor was associated with reduced IBD (OR [95% CI]: .72 [.60, .87], p < .001) and UC risk (OR [95% CI]: .74 [.59, .92], p = .006), although this result was not replicated in the validation cohort. Other drug targets did not show significant associations with IBD, UC or CD risk.ConclusionInhibition of the lipid‐lowering drug‐target NPC1L1 leads to an increased IBD risk, mainly in the UC population.

Lipid-lowering drugs and inflammatory bowel disease’s risk: a drug-target Mendelian randomization study

“…Recently, two MR studies have conducted analyses on the impact of lipid-lowering medications on IBD. In one study, it was found that inhibition of the lipid-lowering drug target NPC1L1 gene expression may increase the risk of developing IBD, which aligns with our research findings [ 47 ]. Another study, utilizing drug-targeted MR analysis, indicated an association between the expression of PCSK9 and an elevated risk of IBD, CD, and UC [ 13 ].…”

Mendelian randomisation analysis for intestinal disease: achievement and future

“…Recently, several repurposing studies have evaluated lipid-lowering medications for inflammatory bowel disease treatment. Specifically, genetic variants linked to key lipid drug targets like PCSK9, 57 74 HMGCR, 74 CETP 57 and NPC1L1 75 served as instruments within an MR framework to probe effects on inflammatory bowel disease. PCSK9 57 74 and NPC1L1 75 inhibition is associated with increased inflammatory bowel disease risk, HMGCR inhibition may confer Crohn's disease risk, while CETP inhibition lowers the risk of Crohn's disease.…”

“…Specifically, genetic variants linked to key lipid drug targets like PCSK9, 57 74 HMGCR, 74 CETP 57 and NPC1L1 75 served as instruments within an MR framework to probe effects on inflammatory bowel disease. PCSK9 57 74 and NPC1L1 75 inhibition is associated with increased inflammatory bowel disease risk, HMGCR inhibition may confer Crohn's disease risk, while CETP inhibition lowers the risk of Crohn's disease. 57 74 In addition, the association between genetically proxied longterm ACE inhibition and the risk of colorectal cancer has been explored.…”